1. Field of the Invention
This invention relates to a series of novel pyridazine analogs which exhibit selective inhibition of interleukin-1.beta. converting enzyme, to compositions containing the novel pyridazine analogs and methods for therapeutic utility. More particularly, the interleukin-1.beta. converting enzyme inhibitors described in this invention comprise novel pyridazine analogs which possess particular utility in the treatment of inflammatory, immune-based diseases and cancer.
2. Reported Developments
Interleukin-1.beta. protease (also known as interleukin-1.beta. converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1.beta. to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A. Proc. Nat. Acad. Sci., 1989, 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R. FEBS Let., 1989, 247, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1.beta. has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, and acute and chronic myelogenous leukemia (Dinarello, C. A.; Wolff, S. M., New Engl. J. Med., 1993, 328, 106). The naturally occurring IL-1.beta. receptor antagonist has been used to demonstrate the intermediacy of IL-1.beta. in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin, G. G.; Dripps, D. J.; Heimdal, P. L.; Armes, L. G.; Sommer, A.; Eisenberg, S. P.; Thompson, R. C., Nature, 1990, 343, 336-340; Eisenberg, S. P.; Evans, R. J.; Arend, W. P.; Verderber, E.; Brewer, M. T.; Hannum, C. H.; Thompson, R. C., Nature 1990, 343, 341-346; Ohlsson, K.; Bjork, P.; Bergenfeldt, M.; Hageman, R.; Thompson, R. C., Nature, 1990, 348, 550-552; and Wakabayashi, G., FASEB, 1991, 338-343). The specific role of IL-1.beta. in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C. A. et al, Cell, 1992, 69, 597-604).
The present invention also relates to the modulation of processing of IL-1.beta. for the treatment of rheumatoid arthritis. Levels of IL-1.beta. are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1.beta. stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and PLA.sub.2, and produces joint destruction which is very similar to rheumatoid arthritis following intraarticular injection in animals.
ICE is believed to be a cysteine protease (Thornbury, N. A. et al, Nature, 1992, 356-768). Peptidyl methyl ketone analogs constitute a well-known class of compounds having cysteine protease inhibitory activity. (D. Rich in Chapter 4 of "Proteinase Inhibitors", Barrett, A. J. and Salvensen, G., eds., Elsevier, 1986). However, there has never been a reported example of a non-peptide heterocyclic inhibitor of a cysteine protease. Hence, the inhibitory activity displayed by the pyridazine analogs described herein against ICE is unique.
An effective therapy has yet to be developed for the treatment of IL-1.beta. mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.